Lenalidomide (LEN) Combined To Intensive Chemotherapy (IC) In AML and Higher Risk MDS With Del 5q. Results Of a Phase I/II Study Of The Groupe Francophone Des Myelodysplasies (GFM)

Contrary to the “5q syndrome”, prognosis of higher risk MDS with del 5q, ie with increased marrow blast % and/or additional cytogenetic abnormalities (abn) and of AML with del 5q (isolated or complex) is poor. Those patients (pts) respond poorly to IC with 20-30% CR, of short duration (Estey, Hematologica 2000) and to azacytidine (Itzykson, Blood 2011). In a phase II study of LEN in higher risk MDS or AML with del 5q, 28% patients responded, but responses were restricted to isolated del 5q (Ades, Blood 2008). This prompted us to combine IC and LEN in higher risk MDS and AML with del 5q.

This phase I/II escalating dose study (NCT00885508) combined induction daunorubicin (DNR 45 mg/m2/d d1-3 in cohort 1, escalated to 60 mg/m2/d d1-3 in cohorts 2 and 3 ) + AraC (200mg/m2/d d1-7) to LEN (10 mg/d d1-21 in cohorts 1 and 2, escalated to 25 mg/d d1-21 in cohort 3). Pts with IPSS int 2 or high MDS or AML with del 5q (isolated or not) were eligible. Responders, ie with CR, CRi or marrow CR according to AML or MDS response criteria received 6 consolidation courses of AraC (120 mg/m2/d d1-5) + DNR (45 or 60 mg/m2 d1), and LEN (10 or 25 mg/d d1-15), with similar daily doses of DNR and LEN as for induction, followed by maintenance LEN (10 or 25mg/d) until progression.

Between Feb 2009 and May 2012, 82 pts were included, 31, 32 and 19 in cohorts 1,2 and 3 respectively. M/F was 42/40, median age was 66 years (IQR: 58-72). 1 patient had RAEB-1, 20 RAEB-2, and 61 had AML (including 21 FAB-RAEB-T, with 20%-30% marrow blasts). 79% pts had complex Karyotype (median number of 7 abn, range 3-17), 10% had isolated del 5q and 11% had del 5q+1 abn. Median baseline WBC was 2.6 G/l (IQR: 1.7-4.2).

5 pts had early death related to severe sepsis in 3, multiorgan failure in 1 and myocardial infarction in 1 pt. 38 of the 82 patients (46%) achieved CR, 4 CRi, 8 PR, 32 had induction failure or progression, leading to an overall response rate (ORR) of 61% (95%CI:49.6-71.6%). The response rate (61%, 62% and 58% respectively) and CR rate (45%, 50 % and 42%) did not significantly differ in cohorts 1,2 and 3. Overall, 59% of the pts achieved cytogenetic response (CyR), 44% complete and 15% partial. 56%, 50% and 75% CyR were seen in patients with complex karyotype, del5q+ 1 abnormality and isolated del 5d respectively. 44%, 25% and 75% of the pts with complex karyotype, del5q+ 1 abnormality and isolated del 5d achieved CR. Two factors significantly predicted lower CR rate: WHO diagnosis (AML 40% vs MDS 66%, p=0.034) and higher marrow blast % (p=0.042).

Overall, 117 consolidations courses were administered and 15 patients received allogeneic SCT. 36 (72%) of the 50 responders subsequently relapsed, with a cumulative incidence of relapse at 1 year of 82.8% (95%CI: 69.7-96.0). In responders, median DFS was 5.8 months (95%CI: 4.6-7.5). Forty-four patients had died, 15 of them within 90 days of treatment onset (early death) leading to an early death rate of 18.9% (95%CI: 14.7-31%). Median overall survival was 7.1 months (95%CI: 6.5-9.4), and 1 year OS estimated at 26.6% (95%CI: 15.6-45.4). Prognostic factors of shorter OS were higher WBC count (p= 0.01), higher marrow blast % (p= 0.005) and poorer performance status (p=0.046) while cytogenetic complexity and treatment cohort had no influence. In a multivariate Cox model, only higher marrow blasts remained of prognostic value. No difference in outcome was observed between treatment cohorts.

Median duration of hospitalization during induction treatment was 30 days (IQR: 26-35) without difference across the 3 cohorts. Grade III-IV non-hematological toxicities included transient liver toxicity with an increase in transaminases (n=11), increase in creatinine level (n=2), Lung disease (n=11) related mainly to sepsis. Of note, grade III-IV increase in transaminases was mainly observed in the 25 mg Lenalidomide cohort (n=6/19, 31%) compared to 5/63 (8%) in pts who received 10 mg, suggesting that the dose limiting toxicity was reached at this dose level.

Intensive anthracycline AraC chemotherapy and LEN can be combined in higher risk MDS and AML with del 5q without unexpected additive myelosuppression. In this cohort of elderly pts with very poor risk cytogenetics (most had very complex karyotype), the ORR rate was 61% and CR rate 46% (with cytogenetic response in most responders), a higher response rate than generally reported with IC alone in similar pts. DFS remained however short, requiring further improvements

Off Label Use: LEN in AML. Fenaux:CELGENE: Research Funding.